The pathogenesis of photoreceptor degenerative diseases remains obscure. An example in human beings is retinitis pigmentosa, characterized by proressive photoreceptor loss, which frequently occurs on a genetic basis. The working hypothesis to be tested here is that photoreceptor survival and differentiation are regulated by molecular signals from their microenvironment, and that defects in these trophic factors might be involved in the pathogenesis of retinal degenerations of genetic origin. This hypothesis will be tested using retinal cells from normal and "Rd" mutant mice. Homozygous Rd mice undergo photoreceptor degenerations early in postnatal life. Extensive use will be made of in vitro systems available in our laboratory. Reaggregation cultures will be used to study the role of cell-cell interactions in photoreceptor development. Interactions of normal and Rd retinal cells with each other and with pigment epithelial cells will be studied in combined aggregates. Monolaver cultures will be used to test the responsiveness of normal and Rd retinal cells to putative sources of trophic agents, such as i) retinal extracts from normal and Rd mice; ii) pigment epithelium conditioned medium; iii) interphotoreceptor maxtrix, and iv) purified extracellullar matrix molecules. Survival and differentiation of photoreceptors and neurons in monolayers and reaggregates will be analyzed with light and electronmicroscopy, autoradiography, lectin cytochemistry and immunocyochemistry using rhodopsin antibodies. It is our expectation that this work will identify molecular agents capable of regulating photoreceptor survival and differentiation, and of altering the natural evolution of retinal degenerations of genetic origin.